A drug which is soluble in water or a solvent available for administration can be formulated into a solution with water or an appropriate solvent to prepare a medicinal product such as an injection, which can be administered. While, in the case where a drug is poorly soluble in water or a solvent available for administration, the drug can be dissolved by adding a solubilizing agent to prepare a drug solution, if available (e.g. Patent document 1), or the drug is milled into a microparticle and formulated into a suspension for administration (e.g. Patent document 2). In some cases, however, some drugs are not dissolved or insufficiently dissolved even by adding a conventional amount of a solubilizing agent, or in other cases, some solubilizing agents can make the pH value of its solution far beyond around bioavailable neutrality.
Also the method using a suspension, however, is not necessarily a universal procedure because in some cases a particle size is not sufficiently small, or in other cases a particle may be aggregated shortly after preparation or during storage. In particular, when a suspension is used for an injection, a sterilizing step such as aseptic filtration is essential, and thus it is necessary to prepare a suspension comprising a drug in the form of stable nanoparticle whose particle size is 0.2 μm (200 nm) or less available for filtration sterilization. However, it has not been realistically easy to prepare such a suspension comprising a drug in the form of the stable nanoparticle, namely it has been difficult to prepare an injectable suspension comprising a poorly-soluble drug.
In connection with recent changes of life styles, arteriosclerotic diseases such as cardiac infarction, angina, stroke, and peripheral vascular disease have been increased. Percutaneous transluminal angioplasty (referred to as “PTA” hereinafter) has been widely used as a reliable method of treating the arteriosclerotic diseases with surgical opening of narrowed or occluded parts of blood vessels, which is represented by, for example, percutaneous transluminal coronary angioplasty in a coronary of heart. PTA is a technique for recovering the blood flow, in which a balloon catheter (a tube having a balloon at its tip) or a stent is inserted from an arm or femoral artery, it is placed at a stenosis in the coronary artery, then the balloon attached at the tip is blown up to expand the stenotic blood vessel. However, the PTA-treated blood vessel is damaged such as detachment of endothelial cell and injury of elastic lamina, and the vascular intima grows because of the healing reaction in the vascular wall, thereby patients whose stenosis lesion site is opened by PTA can suffer from restenosis at a rate of about 30 to 40%.
Then, it has been suggested to try reducing the rate of restenosis by releasing a drug topically for a long time at a site for placement in a lumen, using a drug-dissolution type of a medical device for placement into a lumen wherein an anti-inflammatory agent or an inhibitor of smooth-muscle cell proliferation is supported on the surface of stent or balloon catheter which is made of metal or polymer material (Patent documents 3, 4). For example, Patent document 3 suggests a drug-eluting stent (hereinafter, abbreviated as “DES”) wherein the body of a stent is coated with a biocompatible nanoparticle including a bioactive substance for the treatment, and a process of preparation thereof, which discloses a spherical crystallization technique as a process of a biocompatible nanoparticle. It is however difficult to have an effective amount of nanoparticles of a poorly-soluble drug in water such as cilostazol with the antithrombotic activity remain as the nanoparticles on the surface of a stent or balloon. Various coating methods have been tried, but any useful procedures have not been found.
[Patent document 1] WO 2009/017259
[Patent document 2] WO 2006/052018
[Patent document 3] JP-A-2007-215620
[Patent document 4] WO 2011/024831